The objective of this application is to examine the abuse liability of mephedrone (4-methylmethcathinone) by providing the first comprehensive investigation of its subjective and reinforcing properties in drug discrimination and self-administration assays. Mephedrone is a component of a dangerous street drug called psychoactive bath salts (PABS) and hypothesized to have abuse liability, share pharmacological properties with notorious drugs, and display toxicity that has been linked to fatalities and non-fatal overdoses in users. Mephedrone use is now commonplace in the United States, but knowledge about its abuse liability and risks is based almost entirely on surveys of drug abusers and emergency room visits. Limited experimental data obtained using rats are suggestive of abuse liability (e.g. CNS penetrability, dopamine and 5-HT reuptake block, and enhancement of limbic dopamine and 5-HT levels). However, an absence of second-tier, nonclinical studies examining the abuse liability of mephedrone in relation to underlying mechanisms and comparison to established drugs is a critical gap that needs to be filled to enable clinicians and government officials to predict medical and economic losses posed by mephedrone use. Moreover, no studies to date have examined the enantiomers of mephedrone. Such enantiomers may have different pharmacological properties based on those observed for the enantiomers of methcathinone itself. We now propose to evaluate the subjective and reinforcing properties of mephedrone, and its enantiomers, in drug discrimination and self-administration assays in laboratory rats and to compare these properties with established drugs to identify unique features of mephedrone pharmacology. We hypothesize that mephedrone exhibits a mixed pharmacological profile in which it shares discriminative stimulus effects with psychostimulants such as methamphetamine, cocaine, and ecstasy that alter dopamine, 5-HT and glutamate systems. We also hypothesize that rats will self-administer mephedrone under a progressive ratio (PR) schedule of reinforcement in a pattern similar to other psychostimulants and will exhibit a reinforcing strength equal to or greater than that of MDMA and perhaps equal to cocaine. Similarly, in a reinstatement paradigm, we hypothesize that mephedrone-seeking behavior will be reinstated by a non- contingent injection of mephedrone. Additional studies will test the effects of select DA, 5-HT, and glutamate compounds in the PR and reinstatement procedures to characterize a unique pharmacology underlying the reinforcing effects of mephedrone. The rationale for the proposed research, and expected positive impact of our results, is that comparison of the pharmacological, subjective, reinforcing, and drug-seeking properties of mephedrone with established drugs of abuse will provide an indication of their relative risk of abuse liability and initial insight into potential therapeutic approaches to manag that liability. Further, this will be the first study to prepare and characterize the effects of th enantiomers of mephedrone. PUBLIC HEALTH RELEVANCE: The proposed research is important to public health because psychoactive bath salts are dangerous street drugs that are thought to possess a risk of abuse liability and share pharmacological properties with notorious drugs of abuse. Investigation of the subjective and reinforcing properties of substances contained in those bath salts, especially in relation to underlying mechanisms and comparison to established drugs, will shed new insight into their risk of abuse liability and potential treatments to manage that liability. Thus, the proposed research is relevant to the part of NIDA's mission that pertains to developing strategies to reduce public health, societal and criminal problems and economic losses associated with drug abuse.